title: Mutations in B4GALNT1 (GM2 synthase) underlie a new disorder of ganglioside biosynthesis.
abstract: Glycosphingolipids are ubiquitous constituents of eukaryotic plasma membranes, and their sialylated derivatives, gangliosides, are the major class of glycoconjugates expressed by neurons. Deficiencies in their catabolic pathways give rise to a large and well-studied group of inherited disorders, the lysosomal storage diseases. Although many glycosphingolipid catabolic defects have been defined, only one proven inherited disease arising from a defect in ganglioside biosynthesis is known. This disease, because of defects in the first step of ganglioside biosynthesis (GM3 synthase), results in a severe epileptic disorder found at high frequency amongst the Old Order Amish. Here we investigated an unusual neurodegenerative phenotype, most commonly classified as a complex form of hereditary spastic paraplegia, present in families from Kuwait, Italy and the Old Order Amish. Our genetic studies identified mutations in B4GALNT1 (GM2 synthase), encoding the enzyme that catalyzes the second step in complex ganglioside biosynthesis, as the cause of this neurodegenerative phenotype. Biochemical profiling of glycosphingolipid biosynthesis confirmed a lack of GM2 in affected subjects in association with a predictable increase in levels of its precursor, GM3, a finding that will greatly facilitate diagnosis of this condition. With the description of two neurological human diseases involving defects in two sequentially acting enzymes in ganglioside biosynthesis, there is the real possibility that a previously unidentified family of ganglioside deficiency diseases exist. The study of patients and animal models of these disorders will pave the way for a greater understanding of the role gangliosides play in neuronal structure and function and provide insights into the development of effective treatment therapies.
authors.affiliation: 1 Institute of Biomedical and Clinical Science, University of Exeter Medical School, St. Luke's Campus, Heavitree Road, EX1 2LU, Exeter, Devon, UK.
authors.forename: Gaurav V
authors.initials: GV
authors.lastname: Harlalka
authors.forename: Anna
authors.initials: A
authors.lastname: Lehman
authors.forename: Barry
authors.initials: B
authors.lastname: Chioza
authors.forename: Emma L
authors.initials: EL
authors.lastname: Baple
authors.forename: Reza
authors.initials: R
authors.lastname: Maroofian
authors.forename: Harold
authors.initials: H
authors.lastname: Cross
authors.forename: Ajith
authors.initials: A
authors.lastname: Sreekantan-Nair
authors.forename: David A
authors.initials: DA
authors.lastname: Priestman
authors.forename: Saeed
authors.initials: S
authors.lastname: Al-Turki
authors.forename: Meriel E
authors.initials: ME
authors.lastname: McEntagart
authors.forename: Christos
authors.initials: C
authors.lastname: Proukakis
authors.forename: Louise
authors.initials: L
authors.lastname: Royle
authors.forename: Radoslaw P
authors.initials: RP
authors.lastname: Kozak
authors.forename: Laila
authors.initials: L
authors.lastname: Bastaki
authors.forename: Michael
authors.initials: M
authors.lastname: Patton
authors.forename: Karin
authors.initials: K
authors.lastname: Wagner
authors.forename: Roselyn
authors.initials: R
authors.lastname: Coblentz
authors.forename: Joy
authors.initials: J
authors.lastname: Price
authors.forename: Michelle
authors.initials: M
authors.lastname: Mezei
authors.forename: Kamilla
authors.initials: K
authors.lastname: Schlade-Bartusiak
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Crosby
mesh_terms: D061365:Amish; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005732:Gangliosides / Q000096:biosynthesis; D020143:Gangliosidoses, GM2 / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007558:Italy; D008297:Male; D009154:Mutation / Q000235:genetics*; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics*; D010641:Phenotype; D012867:Skin / Q000473:pathology
chemical_list: D005732:Gangliosides; D017350:N-Acetylgalactosaminyltransferases; C023220:(N-acetylneuraminyl)-galactosylglucosylceramide N-acetylgalactosaminyltransferase
keywords: Amish; B4GALNT1; SPG26; ganglioside biosynthesis; hereditary spastic paraplegia